Human antibodies to middle east respiratory syndrome—coronavirus spike protein

Abstract

The present invention provides monoclonal antibodies that bind to the Middle East Respiratory Syndrome-Coronavirus (MERS-CoV) spike protein, and methods of use. In various embodiments of the invention, the antibodies are fully human antibodies that bind to MERS-CoV spike protein. In some embodiments, the antibodies of the invention are useful for inhibiting or neutralizing MERS-CoV activity, thus providing a means of treating or preventing MERS infection in humans. In some embodiments, the invention provides for a combination of one or more antibodies that bind to the MERS-CoV spike protein for use in treating MERS infection. In certain embodiments, the one or more antibodies bind to distinct non-competing epitopes comprised in the receptor binding domain of the MERS-CoV spike protein.

What is claimed is: 
     
       1. A human monoclonal antibody or antigen-binding fragment thereof that specifically binds to Middle East Respiratory Syndrome corona virus (MERS-CoV) spike protein, wherein the antibody or antigen-binding fragment comprises three heavy chain complementarity determining regions (CDRs) (HCDR1, HCDR2 and HCDR3) contained within any one of the heavy chain variable region (HCVR) sequences selected from the group consisting of SEQ ID NOs: 2, 18, 34, 50, 66, 82, 98, 114, 122, 130, 138, 146, 154, 170, 178, 186, 202, 218, 234, 250, 266, 282, 298, 314, 330, 346, 362, 378, 394, 410, 426, and 442; and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within any one of the light chain variable region (LCVR) sequences selected from the group consisting of SEQ ID NOs: 10, 26, 42, 58, 74, 90, 106, 162, 194, 210, 226, 242, 258, 274, 290, 306, 322, 338, 354, 370, 386, 402, 418, 434, and 450, wherein the antibody or antigen-binding fragment comprises a HCVR/LCVR amino acid sequence pair selected from the group consisting of SEQ ID NOs: 2/10, 18/26, 34/42, 50/58, 66/74, 82/90, 98/106, 114/106, 122/106, 130/106, 138/106, 146/106, 154/162, 170/162, 178/162, 186/194, 202/210, 218/226, 234/242, 250/258, 266/274, 282/290, 298/306, 314/322, 330/338, 346/354, 362/370, 378/386, 394/402, 410/418, 426/434, and 442/450. 
     
     
       2. The antibody or antigen-binding fragment thereof of  claim 1 , wherein the antibody has one or more of the following characteristics:
 (a) interacts with one or more amino acid residues in the receptor binding domain of the MERS-CoV spike protein selected from amino acid residues 367 to 606 of SEQ ID NO: 457; 
 (b) binds to MERS-CoV spike protein with a dissociation constant (K D ) of less than 18.5 nM, as measured in a surface plasmon resonance assay; 
 (c) blocks binding of MERS-CoV spike protein to dipeptidyl peptidase 4 (DPP4) by more than 90%, as measured in a blocking ELISA assay; 
 (d) neutralizes MERS-CoV infectivity of human host cells by more than 90% and with IC50 less than 4 nM, as measured in a virus-like particle (VLP) neutralization assay; 
 (e) neutralizes MERS-CoV infectivity wherein the MERS-CoV comprises an isolate of the virus selected from the group consisting of EMC/2012, Jordan-N3/2012, England-Qatar/2012, Al-Hasa_1_2013, Al-Hasa_2_2013, Al-Hasa_3_2013, Al-Hasa_4_2013, Al-Hasa_12, Al-Hasa_15, Al-Hasa_16, Al-Hasa_17, Al-Hasa_18, Al-Hasa_19, Al-Hasa_21, Al-hasa_25, Bisha_1, Buraidah_1, England 1, Hafr-Al-batin_1, Hafr-Al-Batin_2, Hafr-Al-Batin_6, Jeddah_1, KFU-HKU 1, KFU-HKU 13, Munich, Qatar3, Qatar4, Riyadh_1, Riyadh_2, Riyadh_3, Riyadh_3, Riyadh_4, Riyadh_5, Riyadh_9, Riyadh_14, Taif_1, UAE, and Wadi-Ad-Dawasir; and 
 (f) prevents entry of MERS-CoV into a host cell. 
 
     
     
       3. The antibody or antigen-binding fragment thereof of  claim 1 , comprising a HCVR having an amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 18, 34, 50, 66, 82, 98, 114, 122, 130, 138, 146, 154, 170, 178, 186, 202, 218, 234, 250, 266, 282, 298, 314, 330, 346, 362, 378, 394, 410, 426, and 442. 
     
     
       4. The antibody or antigen-binding fragment thereof of  claim 1 , comprising a LCVR having an amino acid sequence selected from the group consisting of SEQ ID NOs: 10, 26, 42, 58, 74, 90, 106, 162, 194, 210, 226, 242, 258, 274, 290, 306, 322, 338, 354, 370, 386, 402, 418, 434, and 450. 
     
     
       5. The antibody or antigen-binding fragment thereof of  claim 1 , comprising:
 (a) a HCDR1 domain having an amino acid sequence selected from the group consisting of SEQ ID NOs: 4, 20, 36, 52, 68, 84, 100, 116, 124, 132, 140, 148, 156, 172, 180, 188, 204, 220, 236, 252, 268, 284, 300, 316, 332, 348, 364, 380, 396, 412, 428, and 444; 
 (b) a HCDR2 domain having an amino acid sequence selected from the group consisting of SEQ ID NOs: 6, 22, 38, 54, 70, 86, 102, 118, 126, 134, 142, 150, 158, 174, 182, 190, 206, 222, 238, 254, 270, 286, 302, 318, 334, 350, 366, 382, 398, 414, 430, and 446; 
 (c) a HCDR3 domain having an amino acid sequence selected from the group consisting of SEQ ID NOs: 8, 24, 40, 56, 72, 88, 104, 120, 128, 136, 144, 152, 160, 176, 184, 192, 208, 224, 240, 256, 272, 288, 304, 320, 336, 352, 368, 384, 400, 416, 432, and 448; 
 (d) a LCDR1 domain having an amino acid sequence selected from the group consisting of SEQ ID NOs: 12, 28, 44, 60, 76, 92, 108, 164, 196, 212, 228, 244, 260, 276, 292, 308, 324, 340, 356, 372, 388, 404, 420, 436, and 452; 
 (e) a LCDR2 domain having an amino acid sequence selected from the group consisting of SEQ ID NOs: 14, 30, 46, 62, 78, 94, 110, 166, 198, 214, 230, 246, 262, 278, 294, 310, 326, 342, 358, 374, 390, 406, 422, 438, and 454; and 
 (f) a LCDR3 domain having an amino acid sequence selected from the group consisting of SEQ ID NOs: 16, 32, 48, 64, 80, 96, 112, 168, 200, 216, 232, 248, 264, 280, 296, 312, 328, 344, 360, 376, 392, 408, 424, 440, and 456. 
 
     
     
       6. An isolated human antibody or antigen-binding fragment thereof that competes for binding to MERS-CoV-S with the antibody or antigen-binding fragment of  claim 1 . 
     
     
       7. The antibody or antigen-binding fragment thereof of  claim 6 , wherein the antibody or antigen-binding fragment thereof interacts with the spike protein of a MERS-CoV isolate selected from the group consisting of EMC/2012, Jordan-N3/2012, England-Qatar/2012, Al-Hasa_1_2013, Al-Hasa_2_2013, Al-Hasa_3_2013, Al-Hasa_4_2013, Al-Hasa_12, Al-Hasa_15, Al-Hasa_16, Al-Hasa_17, Al-Hasa_18, Al-Hasa_19, Al-Hasa_21, Al-hasa_25, Bisha_1, Buraidah_1, England 1, Hafr-Al-batin_1, Hafr-Al-Batin_2, Hafr-Al-Batin_6, Jeddah_1, KFU-HKU 1, KFU-HKU 13, Munich, Qatar3, Qatar4, Riyadh_1, Riyadh_2, Riyadh_3, Riyadh_3, Riyadh_4, Riyadh_5, Riyadh_9, Riyadh_14, Taif_1, UAE, and Wadi-Ad-Dawasir. 
     
     
       8. The antibody or antigen-binding fragment thereof of  claim 7 , wherein the antibody or antigen-binding fragment thereof blocks the binding of MERS-CoV to DPP4 on human cells. 
     
     
       9. The antibody or antigen-binding fragment thereof of  claim 8 , wherein the antibody or antigen-binding fragment thereof is isolated from a hybridoma cell line selected from the group consisting of HBVX06H05, HBVX11H04, HBVX11D02, HBVZ10E10, HBVY09F08, HBVZ05G02, HBVZ09B06, HBVY01F08, HBVY10G02, HBVY04B06, HBVY07D10, HBVZ08A09, HBVZ05G04, HBVY06C07, HBVY03H06, HBVZ10G06, HBVZ04F10, HBVX11E09, HBVY06H09, HBVZ05B11, HBVY02E05 and HBVZ04C07. 
     
     
       10. An isolated recombinant human monoclonal antibody or antigen-binding fragment thereof that binds to the same epitope as the antibody or antigen-binding fragment of  claim 1 . 
     
     
       11. A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof of  claim 1  and a pharmaceutically acceptable carrier or diluent. 
     
     
       12. A pharmaceutical composition comprising: (a) a first antibody or antigen-binding fragment thereof that binds to MERS-CoV spike protein at a first epitope; (b) a second antibody or antigen-binding fragment thereof that binds to MERS-CoV spike protein at a second epitope, and (c) a pharmaceutically acceptable carrier or diluent, wherein the first antibody or antigen-binding fragment thereof is a human antibody or antigen-binding fragment comprising a HCVR/LCVR amino acid sequence pair selected from the group consisting of SEQ ID NOs: 2/10, 18/26, 34/42, 50/58, 66/74, 82/90, 98/106, 114/106, 122/106, 130/106, 138/106, 146/106, 154/162, 170/162, 178/162, 186/194, 202/210, 218/226, 234/242, 250/258, 266/274, 282/290, 298/306, 314/322, 330/338, 346/354, 362/370, 378/386, 394/402, 410/418, 426/434, and 442/450. 
     
     
       13. The pharmaceutical composition of  claim 12 , wherein at least the first antibody or antigen-binding fragment thereof or the second antibody or antigen-binding fragment thereof blocks MERS-CoV-S binding to DPP4. 
     
     
       14. The pharmaceutical composition of  claim 13 , wherein the first and second epitopes are present in the receptor binding domain of MERS-CoV spike protein and are distinct and non-overlapping. 
     
     
       15. The pharmaceutical composition of  claim 14 , wherein the first antibody or antigen-binding fragment thereof comprises a HCVR, wherein the HCVR comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 18, 66, 114, 170, and 218; and a LCVR, wherein the LCVR comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 10, 26, 74, 106, 162, and 226. 
     
     
       16. The antibody or antigen-binding fragment thereof of  claim 5  comprising a HCVR/LCVR amino acid sequence pair selected from the group consisting of SEQ ID NOs: 66/74 and 218/226. 
     
     
       17. The antibody or antigen-binding fragment thereof of  claim 16  comprising a HCVR/LCVR amino acid sequence pair of SEQ ID NOs: 66/74. 
     
     
       18. The antibody or antigen-binding fragment thereof of  claim 16  comprising a HCVR/LCVR amino acid sequence pair of SEQ ID NOs: 218/226. 
     
     
       19. The antibody or antigen-binding fragment thereof of  claim 5  comprising HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 domains of SEQ ID NOs: 68-70-72-76-78-80. 
     
     
       20. The antibody or antigen-binding fragment thereof of  claim 5  comprising HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 domains of SEQ ID NOs: 220-222-224-228-230-232. 
     
     
       21. A pharmaceutical composition comprising one or more antibodies or antigen-binding fragments thereof of  claim 5  and a pharmaceutically acceptable carrier or diluent. 
     
     
       22. The pharmaceutical composition of  claim 15 , wherein the first antibody or antigen-binding fragment thereof comprises a HCVR/LCVR amino acid sequence pair selected from the group consisting of SEQ ID NOs: 66/74 and 218/226. 
     
     
       23. The pharmaceutical composition of  claim 22 , wherein the first antibody or antigen-binding fragment thereof comprises a HCVR/LCVR amino acid sequence pair of SEQ ID NOs: 66/74. 
     
     
       24. The pharmaceutical composition of  claim 22 , wherein the first antibody or antigen-binding fragment thereof comprises a HCVR/LCVR amino acid sequence pair of SEQ ID NOs: 218/226. 
     
     
       25. The pharmaceutical composition of  claim 23 , wherein the second antibody or antigen-binding fragment thereof comprises a HCVR/LCVR amino acid sequence pair of SEQ ID NOs: 218/226.